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- Title
Rapamycin suppresses 5'TOP mRNA translation through inhibition of p70<sup>s6k</sup>.
- Authors
Jefferies, Harold B. J.; Fumagali, Stefano; Dennis, Patrick B.; Reinhard, Christoph; Pearson, Richard B.; Thomas, George
- Abstract
Treatment of mammalian cells with the immunosuppressant rapamycin, a bacterial macrolide, selectively suppresses mitogeninduced translation of an essential class of mRNAs which contain an oligopyrimidine tract at their transcriptional start (5′TOP), most notably mRNAs encoding ribosomal proteins and elongation factors. In parallel, rapamycin blocks mitogen-induced p70 ribosomal protein S6 kinase (p70s6k) phosphorylation and activation. Utilizing chimeric mRNA constructs containing either a wild-type or disrupted 5′TOP, we demonstrate that an intact polypyrimidine tract is required for rapamycin to elicit an inhibitory effect on the translation of these transcripts. In turn, a dominant-interfering p70s6k, which selectively prevents p70s6k activation by blocking phosphorylation of the rapamycinsensitive sites, suppresses the translation of the chimeric mRNA containing the wild-type but not the disrupted 59TOP. Conversion of the principal rapamycinsensitive p70s6k phosphorylation site, T389, to an acidic residue confers rapamycin resistance on the kinase and negates the inhibitory effects of the macrolide on 5′TOP mRNA translation in cells expressing this mutant. The results demonstrate that the rapamycin block of mitogeninduced 59TOP mRNA translation is mediated through inhibition of p70s6k activation.
- Subjects
RAPAMYCIN; IMMUNOSUPPRESSIVE agents; DRUGS; MACROLIDE antibiotics; PROTEIN kinases; PHOSPHOTRANSFERASES; PHOSPHORYLATION; CHEMICAL reactions
- Publication
EMBO Journal, 1997, Vol 16, Issue 12, p3693
- ISSN
0261-4189
- Publication type
Article
- DOI
10.1093/emboj/16.12.3693